Protease/protease inhibitor imbalances are a common feature of chronic diseases of humans. Examples of diseases and pathological conditions in which an imbalance of proteases and their inhibitors is implicated include rheumatoid and other forms of arthritis, tumor metastasis, tumor angiogenesis, periodontal disease, corneal, epidermal, and gastric ulceration, osteoporosis, Paget's disease of bone, glomerulonephritis, atopic dermatitis, psoriasis, scleroderma, pressure atrophy of bone or tissues, cholesteatoma, nerve cell disorders, organ injury due to ischemia-reperfusion (including local sequelae of myocardial anoxia), malaria, chronic wound healing, Chagas disease, parasitic eye infection, viral infection (e.g. HIV, herpes), bacterial infection, Alzheimer's disease, hypertension, sepsis, acute leukemia, dystrophic epidermolysis bullosa, and muscular dystrophy.
In particular, protease/protease inhibitor imbalances are notable in a number of respiratory diseases. The classic and prototypic example of this is alpha 1-antitrypsin (AAT) deficiency, where low levels of AAT (also known as alpha 1-protease inhibitor) in the bloodstream, determined by genetic factors, lead to decreased levels of AAT in the lung. The consequence of this is a decreased inhibitory capacity towards the proteolytic enzyme neutrophil elastase. This compromised ability to control elastolytic activity, and the consequent degradation of lung elastin, leads inevitably to the early onset of pulmonary emphysema in many individuals with AAT-deficiency.
Other respiratory diseases where protease/protease inhibitor imbalances have been shown to have significant involvement in disease progression are asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and respiratory distress syndrome. In asthma, the mast cell-derived proteases, tryptase and chymase, have been shown to be involved in the inflammatory response to allergenic stimuli. Similarly, the inhibition of airway hyperresponsiveness by AAT has implicated protease targets for AAT, such as neutrophil elastase, cathepsin G, and kallikrein as possible contributory factors in this condition.
Elevated levels of several matrix metalloproteases (MMPs) have been shown in human COPD, particularly in COPD induced by cigarette smoking. Although implicated in the degradation of lung collagen and elastin, the relative contributions of metalloproteases and elastase to the reduction of lung elasticity, and consequent development of pulmonary emphysema is not fully understood at the present time. Interestingly, transgenic mouse models for smoking-related emphysema have implicated the murine metalloelastase (equivalent to human MMP-12) as a critical factor in the development of smoking related COPD in this species.
Protease inhibitors are also implicated in the treatment of HIV. One of the major proteins coded for by HIV nucleic acid is a protease, and one of the most effective treatments of HIV to date is the use of protease inhibitors.
A full understanding of the equilibrium between the above proteases and their inhibitors is made even more complex by the findings that matrix metalloprotease inhibitors are capable of cleaving, and thereby inactivating AAT and, conversely, neutrophil elastase can inactivate endogenous tissue inhibitors of metalloproteases (TIMPs). A major pathogen of the lung, Pseudomonas aeruginosa, which colonizes the lungs of many individuals with CF, secretes a metalloelastase that degrades AAT, leading to much of the lung damage associated with CF.
The incidence of many diseases in which a protease/protease inhibitor imbalance is implicated is increasing; for example, the incidence of emphysema in the U.S. is up over 40% compared to 1982. While there have been advancements in the amelioration of these diseases, there are at present no completely satisfactory treatments. Hence there is a need for improved methods of treatment to reduce symptoms and/or to slow or halt disease progress. The present invention addresses these needs.